Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy

Abstract

Neurodevelopmental disorders (NDDs) affect 2–4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.

Metadata

Item Type:	Article
Authors/Creators:	Jackson, A. https://orcid.org/0000-0002-3674-3960 Blakes, A.J.M. https://orcid.org/0000-0002-0260-7020 Alhaddad, B. Henry, O.J. https://orcid.org/0000-0002-4717-8346 Delgado-Vega, A.M. https://orcid.org/0000-0002-9865-0591 Wall, E. Abdelhadi, O. Agrawal, S. Bakur, K. Blair, E. Brady, A.F. Brittain, H. Chandler, K.E. Clarke, N. Danelli, M. Drinkall, N. Duba, I. https://orcid.org/0009-0005-4189-8704 Elmslie, F. https://orcid.org/0000-0002-2508-9107 Ellingford, J. https://orcid.org/0000-0003-1137-9768 Ewans, L.J. Fennell, A.P. https://orcid.org/0000-0001-6744-1810 Gazdagh, G. Heller, S.P. https://orcid.org/0000-0001-7335-9266 Hammarsjö, A. Karrman, K. Kini, U. Lesko, N. Lindstrand, A. Macintosh, R. https://orcid.org/0000-0001-5036-0264 Mansour, S. Menzies, L. Metcalfe, K. Milhench, A. Nashef, L. O’Keefe, R.T. https://orcid.org/0000-0001-8764-1289 Pacheco, N.P. Palmer, E.E. https://orcid.org/0000-0003-1844-215X Parida, A. Prescott, K. Redman, M. Renieri, A. https://orcid.org/0000-0002-0846-9220 Fallerini, C. Rizzo, C.L. Sachdev, R. Simons, C. https://orcid.org/0000-0003-3147-8042 Sisodiya, S.M. https://orcid.org/0000-0002-1511-5893 Stewart, H. Stödberg, T. Banos-Pinero, B. Taylan, F. https://orcid.org/0000-0002-2907-0235 Thomas, H.B. https://orcid.org/0000-0001-9626-9706 Tinella, F. Wiafe, S. Wedell, A. Whiffin, N. Walker, S. https://orcid.org/0000-0002-5016-6426 Rius, R. https://orcid.org/0000-0002-9871-3126 Chae, J.H. Nordgren, A. https://orcid.org/0000-0003-3285-4281 Alkuraya, F. https://orcid.org/0000-0003-4158-341X Lord, J. https://orcid.org/0000-0002-0539-9343 Banka, S. https://orcid.org/0000-0002-8527-2210
Copyright, Publisher and Additional Information:	© The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Neurodevelopmental disorders
Dates:	Submitted: 2 September 2025 Accepted: 23 February 2026 Published (online): 30 March 2026 Published: April 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Funding Information:	Funder Grant number Wellcome Trust Ltd 223521/Z/21/Z
Date Deposited:	16 Apr 2026 08:51
Last Modified:	16 Apr 2026 08:51
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41588-026-02551-9
Related URLs:	PubMed URL Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:240089